Benzimidazole compounds having nociceptin receptor affinity

ABSTRACT

Disclosed are compounds of the formula (I)  
                 
 
     wherein A, R 1 , R 2 , R 3 , R 4  and X 1  are as disclosed herein. The compounds have affinity for the ORL1 receptor and are useful in the treatment of chronic and acute pain.

[0001] This application claims the benefit of U.S. provisional No.60/169,394 filed Dec. 6, 1999, the disclosure of which is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Chronic pain is a major contributor to disability in theindustrialized world and is the cause of an untold amount of suffering.The successful treatment of severe and chronic pain is a primary goal ofthe physician with opioid analgesics being the current drugs of choice.Unfortunately, this class of compounds produces several undesirable sideeffects including respiratory depression, constipation, and thedevelopment of tolerance and dependence.

[0003] Opioids are derived from the opium poppy papaya somniferum andinclude drugs such as morphine, codeine and semi-synthetic compoundsderived from them and from thebaine, another component of the opiumpoppy. It was hypothesized that the opioids derived their therapeuticeffect by interacting with specific receptor sites in the body. Laterexperiments led to the belief that there were more than one receptorsite in the body, in explanation for the fact that the syntheticcompound nalorphine provides analgesic activity while at the same time,antagonizes the analgesic effect of morphine.

[0004] Until recently, there was evidence of three major classes ofopioid receptors in the central nervous system (CNS), with each classhaving subtype receptors. These receptor classes were designated as μ, δand k. As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to, identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

[0005] Recent experimentation has led to the identification of a cDNAencoding an opioid receptor-like (ORL1) receptor with a high degree ofhomology to the known receptor classes. This newly discovered receptorwas classified as an opioid receptor based only on structural grounds,as the receptor did not exhibit pharmacological homology. It wasinitially demonstrated that non-selective ligands having a high affinityfor μ, δ and k receptors had low affinity for the ORL1. Thischaracteristic, along with the fact that an endogenous ligand had notyet been discovered, led to the term “orphan receptor”.

[0006] Subsequent research led to the isolation and structure of theendogenous ligand of the ORL1 receptor. This ligand is a seventeen aminoacid peptide structurally similar to members of the opioid peptidefamily.

[0007] The discovery of the ORL1 receptor presents an opportunity indrug discovery for novel compounds which can be administered for painmanagement or other syndromes modulated by this receptor.

[0008] Given the close structural homology of ligands to the ORL1receptor to ligands of the other opioid receptors, such drug discoverycould also lead to compounds having a higher affinity for the μ, δ and kreceptors than known compounds, while producing less side effects.

OBJECTS AND SUMMARY OF THE INVENTION

[0009] It is accordingly an object of the present invention to providenew compounds which exhibit affinity for the ORL1 receptor.

[0010] It is another object of the present invention to provide newcompounds which exhibit affinity for the ORL1 receptor and one or moreof the μ, δ or k receptors.

[0011] It is another object of the present invention to provide newcompounds for treating a patient suffering from chronic or acute pain byadministering a compound having affinity for the ORL1 receptor.

[0012] It is another object of the invention to provide new compoundswhich have agonist activity at the μ, δ and k receptors which is greaterthan compounds currently available e.g. morphine.

[0013] It is another object of the invention to provide methods oftreating chronic and acute pain by administering compounds which haveagonist activity at the μ, δ and k receptors which is greater thancompounds currently available.

[0014] It is another object of the invention to provide methods oftreating chronic and acute pain by administering non-opioid compoundswhich have agonist activity at the μ, δ and k receptors and whichproduce less side effects than compounds currently available.

[0015] It is another object of the present invention to providecompounds useful as analgesics, antiinflammatories, diuretics,anesthetics and neuroprotective agents and methods for administeringsaid compounds.

[0016] It is another object of the present invention to provide a methodof modulating a response from opioid receptors comprising administeringa compound having a binding affinity for the ORL1 receptor of less than500 K_(i) (nM) and a binding affinity for the mu receptor of less than25 K_(i) (nM).

[0017] It is another object of the invention to provide a method ofreducing side effects associated with the administration of opioidanalgesics in a human patient comprising administering to a humanpatient an analgesically effective amount of a non-opioid compound whichexhibits a binding affinity for the ORL1 receptor of less than 500 K_(i)(nM). In other embodiments, the compound has a binding affinity for themu receptor of less than 25 K_(i) (nM).

[0018] Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. With the aboveand other objects in view, the present invention in certain embodimentscomprises compounds having the general formula (I):

[0019] wherein

[0020] A is a saturated, unsaturated or partially unsaturated ring

[0021] X₁ is selected from the group consisting of a bond, C₁₋₁₀branched or straight alkyl, alkenyl, alkynylene optionally substitutedwith 1-3 halogen, oxo or phenyl groups, said phenyl group optionallysubstituted with 1-3 halogen or C₁₋₁₀ alkyl groups;

[0022] R₁ is selected from the group consisting of hydrogen, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, a monocyclic, bicyclic or tricyclic arylor heteroaryl ring, a heteromonocyclic ring, and a heterobicyclic ringsystem, wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic,bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring,and heterobicyclic ring system are optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, whereinsaid phenyl, benzyl, phenyloxy and benzyloxy are optionally substitutedwith halogen or C₁₋₁₀ alkyl;

[0023] R₂ is selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen, said alkyl and cycloalkyl substituted with anoxo group; and

[0024] R₃ and R₄ are independently selected from the group consisting ofhydrogen, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ carbonyl and halogen;and pharmaceutically acceptable salts thereof.

[0025] In preferred embodiments, A has one double bond at the 1,2position.

[0026] In preferred embodiments, X₁R₁ is not hydrogen.

[0027] In preferred embodiments, A has one double bond at the 1,2position.

[0028] In other preferred embodiments X₁ is selected from a bond,methyl, ethyl or propyl.

[0029] In other preferred embodiments X₁ is substituted withfluorophenyl.

[0030] In other preferred embodiments R₁ is a tricyclic aryl ring,preferably dibenzocycloheptyl.

[0031] In other preferred embodiments R₁ is a cycloalkyl, preferablycyclopentyl, cyclohexyl or cycloheptyl, wherein the cycloalkyl isoptionally substituted with a C₁₋₃ alkyl.

[0032] In other preferred embodiments R₁ is a monocyclic aryl ring,preferably phenyl, wherein the aryl ring is optionally substituted witha halogen, C₁₋₃ alkyl, phenyl or benzyloxy.

[0033] In other preferred embodiments, R₁ is selected from napthyl,benzyloxyphenyl, decahydronaphyl, 1,3 hydro-indene, propylhexane,cyclodecyl, biphenylmethyl, phenylethyl, cyclooctyl,1,2,3,4,hydro-napthyl, 1-3 dimethyl-pentyl.

[0034] In other preferred embodiments, R₂ is a methyl, ethyl or propylwherein the methyl ethyl and propyl are optionally substituted with anoxo group.

[0035] In other preferred embodiments, R₃ and R₄ are both hydrogen.

[0036] As used herein, the term “alkyl” means a linear or branchedsaturated aliphatic hydrocarbon group having a single radical and 1-10carbon atoms. Examples of alkyl groups include methyl, propyl,isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.A branched alkyl means that one or more alkyl groups such as methyl,ethyl or propyl, replace one or both hydrogens in a —CH₂— group of alinear alkyl chain.

[0037] The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbomyl.

[0038] The term “alkenyl” means a linear or branched aliphatichydrocarbon group containing a carbon-carbon double bond having a singleradical and 2-10 carbon atoms. A “branched” alkenyl means that one ormore alkyl groups such as methyl, ethyl or propyl replace one or bothhydrogens in a —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenylgroups include ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl,3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.

[0039] The term “cycloalkenyl” means a non-aromatic monocyclic ormulticyclic hydrocarbon ring system containing a carbon-carbon doublebond having a single radical and 3 to 12 carbon atoms. Exemplarymonocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl,cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenylring is norbomenyl.

[0040] The term “aryl” means a carbocyclic aromatic ring systemcontaining one, two or three rings which may be attached together in apendent manner or fused, and containing a single radical. Exemplary arylgroups include phenyl and naphthyl.

[0041] The term “heterocyclic” means cyclic compounds having one or moreheteroatoms (atoms other than carbon) in the ring, and having a singleradical. The ring may be saturated, partially saturated and unsaturated,and the heteroatoms may be selected from the group consisting ofnitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl; saturated 3- to 6-membered heteromonocyclic groupscontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asmorpholinyl; saturated 3- to 6-membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolidinyl. Examples of partially saturated heterocyclic radicalsinclude dihydrothiophene, dihydropyran, and dihydrofuran.

[0042] The term “heteroaryl” means unsaturated heterocyclic radicals,wherein heterocyclic is as previously described. Exemplary heteroarylgroups include unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl,and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to5 nitrogen atoms, such as indolyl, quinolyl, isoquinolyl; unsaturated 3to 6-membered heteromonocyclic groups containing an oxygen atom, such asfuryl; unsaturated 3 to 6 membered heteromonocyclic groups containing asulfur atom, such as thienyl; unsaturated 3 to 6 memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; unsaturated condensed heterocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term“heteroaryl” also includes unsaturated heterocyclic radicals, whereinheterocyclic is as previously described, in which the heterocyclic groupis fused with an aryl group, in which aryl is as previously described.Exemplary fused radicals include benzofuran, benzdioxole andbenzothiophene.

[0043] As used herein, the term “patient” includes both human and othermammals.

[0044] As used herein, the term “halogen” includes fluoride, bromide,chloride, iodide or alabamide.

[0045] The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, secium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

[0046] The invention disclosed herein is also meant to encompass allprodrugs of the disclosed compounds. Prodrugs are considered to be anycovalently bonded carriers which release the active parent drug in vivo.

[0047] The invention disclosed herein is also meant to encompass the invivo metabolic products of the disclosed compounds. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

[0048] The invention disclosed herein is also meant to encompass thedisclosed compounds being isotopically-labelled by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well As usedherein, the term “stereoisomers” is a general term for all isomers ofindividual molecules that differ only in the orientation of their atomsin space. It includes enantiomers and isomers of compounds with morethan one chiral center that are not mirror images of one another(diastereomers).

[0049] The term “chiral center” refers to a carbon atom to which fourdifferent groups are attached.

[0050] The term “enantiomer” or “enantiomeric” refers to a molecule thatis nonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

[0051] The term “racemic” refers to a mixture of equal parts ofenantiomers and which is optically inactive.

[0052] The term “resolution” refers to the separation or concentrationor depletion of one of the two enantiomeric forms of a molecule.

[0053] Certain preferred compounds of formula I according to theinvention include:

[0054]1-[1-dibenzocycloheptyl-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0055]1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[1-oxo-propyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0056]1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[l-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0057]1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[2-oxo-cyclopropyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0058]1-[1-(4-propyl-1,2-cyclohexene)-4-piperidinyl-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0059] 1-[l-(4,4-difluorophenylbutyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and

[0060] 1-[l-(4-phenyl-phenylmethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one.

[0061]1-[1-(2-napthyl-methyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0062]1-[1-(4-benzyloxy-benzyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0063]1-[1-(decahydronaphyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0064] 1-[1-(2[1,3dihydro-indene])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0065]1-[1-(4-isopropylhexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0066]1-[1-(4-[1-methyl-ethyl]hexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0067] 1-[1-cyclodecyl-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0068]1-[1-(3-diphenylpropyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0069]1-[1-(2-phenylethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0070]1-[1-(cyclooctylethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0071]1-[1-(4-[1,2,3,4,hydro-napthyl])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0072] 1-[1-(4-[1-3dimethyl-pentyl])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and pharmaceutically acceptable salts thereof.

[0073] The present invention is also directed to the followingcompounds:

[0074]1-[4-dibenzocycloheptyl-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0075]1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0076]1-[4-(4-propyl-1,2-cyclohexene)-4-piperidinyl-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0077]1-[4-(4,4-difluorophenylbutyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;

[0078]1-[4-(4-phenyl-phenylmethyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0079] The compounds of the present invention can be administered toanyone requiring modulation of the opioid and ORL1 receptors.Administration may be orally, topically, by suppository, inhalation, orparenterally.

[0080] The present invention also encompasses all pharmaceuticallyacceptable salts of the foregoing compounds. One skilled in the art willrecognize that acid addition salts of the presently claimed compoundsmay be prepared by reaction of the compounds with the appropriate acidvia a variety of known methods.

[0081] Various oral dosage forms can be used, including such solid formsas tablets, gelcaps, capsules, caplets, granules, lozenges and bulkpowders and liquid forms such as emulsions, solution and suspensions.The compounds of the present invention can be administered alone or canbe combined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

[0082] When the compounds of the present invention are incorporated intooral tablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

[0083] In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

[0084] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms, aredescribed in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986), incorporated by reference herein.Techniques and compositions for making solid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachmanand Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc.,incorporated by reference herein. Techniques and compositions for makingtablets (compressed and molded), capsules (hard and soft gelatin) andpills are also described in Remington's Pharmaceutical Sciences (ArthurOsol, editor), 1553B1593 (1980), incorporated herein by reference.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems, (Lieberman,Rieger and Banker, editors) published by Marcel Dekker, Inc.,incorporated herein by reference.

[0085] When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

[0086] The dose of the compounds of the present invention is dependentupon the affliction to be treated, the severity of the symptoms, theroute of administration, the frequency of the dosage interval, thepresence of any deleterious side-effects, and the particular compoundutilized, among other things.

[0087] The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1

[0088]1-[4-(4-propylcyclohexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one.

[0089] The above compound was synthesized according to the followingsynthetic scheme and general procedure:

[0090] General Procedure for Reductive Coupling.

[0091] A solution containing the amine and ketone in toluene wasrefluxed in the presence of molecular sieves for 5-6 hours. The reactionmixture was cooled and filtered through Celite and the Celite cake waswashed with Dichloromethane. The combined filtrate was concentrated todryness. The residue was dissolved in a mixture of THF and methanol(10:1). To the solution was then added 1 eq of NaCNBH3 in one portionand a few drops of acetic acid to adjust pH=4-5. The reaction wasstirred at room temperature for 12 hours. The reaction mixture wasdiluted with EtOAc and washed with 1N NaOH solution. The aqueous wasextracted with additional EtOAc and the combined organic was dried withMgSO4, filtered and concentrated. The desired product was purifiedeither by recrystalization or flash chromatography on silica gel.

PREPARATION OF EXAMPLE 1

[0092] To a solution of 380 mg of example 1 in 10 ml dichloromethane wasadded 236 mg Et₃N, 99 mg acetyl chloride and a catalytic amount of DMAP.The reaction was stirred at room temperature for 12 hours. Afterdiluting with dichloromethane the mixture was washed with brine and theaqueous phase extracted with additional dichloromethane. The combinedorganic extracts were dried over MgSO4, filtered and concentrated. Theresidue was purified via flash chromatography(silica, EtOAc) to givedesired product.

[0093] 1HNMR in CDCl₃(Ppm): 7.35 (t, 2H), 7.10 (m, 7H), 5.05 (s, 2H),3.13-2.80 (m, 9H), 2.62 (s, 3H), 2.40 (m, 2H), 2.13 (m, 1H), 1.89 (bd,2H), 1.70 (m, 1H). LCMS: 404(M+1).

[0094] The general procedures disclosed above can be modified in orderto synthesize the other preferred compounds of the invention.

EXAMPLE 2

[0095] Nociceptin affinity at the ORL1 receptor for preferred compoundswas obtained using the following assay:

[0096] Membranes from recombinant HEK-293 cells expressing the humanopioid receptor-like receptor (ORL-1) (Receptor Biology) were preparedby lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000× g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrationswere determined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

[0097] Functional SGTPγS binding assays were conducted as follows. ORL-1membrane solution was prepared by sequentially adding finalconcentrations of 0.066 μg/μl ORL-1 membrane protein, 10 μg/ml saponin,3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 MMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μl/well) was transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at room temperature withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 μl ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty μl/wellscintillation cocktail (BetaScint; Wallac) was added and plates werecounted in a Packard Top-Count for 1 min/well.

[0098] Data was analyzed using the curve fitting functions in GraphPadPRISM™, v. 3.0 and the results are set forth in table 1 below: TABLE 1Nociceptin Affinity calc K_(i) Compound (nM)1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3-dihydro-2H- 3941,3-benzamidazol-2-one1-[4-(4-propylcyclohexane)-4-piperidinyl]-3-[1-oxo-ethyl]- 4641,3-dihydro-2H-1,3-benzamidazol-2-one1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3-dihydro-2H- 1661,3-benzamidazol-2-one1-[4-(4-propyl-1,2-cyclohexene)-4-piperidinyl-1,3-dihydro- 4692H-1,3-benzamidazol-2-one1-[4-(4,4-difluorophenylbutyl)-4-piperidinyl]-1,3-dihydro-2H- 4201,3-benzamidazol-2-one1-[4-(4-phenyl-phenylmethyl)-4-piperidinyl]-1,3-dihydro-2H- 12521,3-benzamidazol-2-one

EXAMPLE 3

[0099] Affinity at the μ, k and δ receptors for preferred compounds wasobtained according to the following assays:

[0100] Mu, kappa or delta opioid receptor membrane solution was preparedby sequentially adding final concentrations of 0.075 μg/μl of thedesired membrane protein, 10 μg/ml saponin, 3 μM GDP and 0.20 nM[³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH7.4) on ice. The prepared membrane solution (190 μl/well) wastransferred to 96-shallow well polypropylene plates containing 10 μl of20× concentrated stock solutions of agonist prepared in DMSO. Plateswere incubated for 30 min at room temperature with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Packard) using a 96-well tissue harvester (Brandel) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hours. Fifty μl/well scintillation cocktail(MicroScint20, Packard) was added and plates were counted in a PackardTop-Count for 1 min/well.

[0101] Data were analyzed using the curve fitting functions in GraphPadPRISM™, v. 3.0 and the results are set forth in table 2 below: TABLE 2calc K_(i)(nM) Compound μ k δ₂1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3- 19 270 >10,000dihydro-2H-1,3-benzamidazol-2-one1-[4-(4-propylcyclohexane)-4-piperidinyl]-3-[1- 23.2 1600 >10,000oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2- one1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3- 457 940 2210dihydro-2H-1,3-benzamidazol-2-one1-[4-(4-propyl-1,2-cyclohexene)-4-piperidinyl- 265 1500 12201,3-dihydro-2H-1,3-benzamidazol-2-one1-[4-(4,4-difluorophenylbutyl)-4-piperidinyl]-1,3- 52 1200 2050dihydro-2H-1,3-benzamidazol-2-one1-[4-(4-phenyl-phenylmethyl)-4-piperidinyl]-1,3- 105 1300 3290dihydro-2H-1,3-benzamidazol-2-one

What is claimed is:
 1. A compound of the formula (I):

wherein A is a saturated, unsaturated or partially unsaturated ring X₁is selected from the group consisting of a bond, C₁₋₁₀ branched orstraight alkyl, alkenyl, alkynylene optionally substituted with 1-3halogen, oxo or phenyl groups, said phenyl group optionally substitutedwith 1-3 halogen or C₁₋₁₀ alkyl groups; R₁ is selected from the groupconsisting of hydrogen, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, amonocyclic, bicyclic or tricyclic aryl or heteroaryl ring, aheteromonocyclic ring, and a heterobicyclic ring system, wherein saidC₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclic or tricyclicaryl or heteroaryl ring, heteromonocyclic ring, and heterobicyclic ringsystem are optionally substituted with 1-3 substituents selected fromthe group consisting of halogen, C₁₋₁₀ alkyl, nitro, trifluoromethyl,phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl,phenyloxy and benzyloxy are optionally substituted with halogen or C₁₋₁₀alkyl; R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl and halogen, said alkyl optionally substitutedwith an oxo group; and R₃ and R₄ are independently selected from thegroup consisting of hydrogen, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃carbonyl and halogen; and pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1 wherein A has a double bond at the 1,2 position. 3.A compound of claim 1 wherein X₁ is selected from a bond, methyl, ethylor propyl.
 4. A compound of claim 1 wherein X₁ is methyl.
 5. A compoundof claim 1 wherein X₁ is substituted with fluorophenyl.
 6. A compound ofclaim 1 wherein R₁ is a tricyclic aryl ring
 7. A compound of claim 1wherein R₁ is a cycloalkyl
 8. A compound of claim 1 wherein R₁ is amonocyclic aryl ring, wherein the aryl ring is optionally substitutedwith a halogen, C₁₋₃ alkyl, phenyl or benzyloxy.
 9. A compound of claim1 wherein R₁ is selected from napthyl, benzyloxyphenyl, decahydronaphyl,1,3 hydro-indene, propylhexane, cyclodecyl, biphenylmethyl, phenylethyl,cyclooctyl, 1,2,3,4,hydro-napthyl, 1-3 dimethyl-pentyl.
 10. A compoundof claim 4 wherein R₁ is selected from napthyl, benzyloxyphenyl,decahydronaphyl, 1,3 hydro-indene, propylhexane, cyclodecyl,biphenylmethyl, phenylethyl, cyclooctyl, 1,2,3,4,hydro-napthyl, 1-3dimethyl-pentyl.
 11. A compound of claim 1 wherein R₃ and R₄ are bothhydrogen.
 12. A compound of claim 1 selected from1-[1-dibenzocycloheptyl-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[1-oxo-propyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-propylcyclohexane)-4-piperidinyl]-3-[2-oxo-cyclopropyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-propyl-1,2-cyclohexene)-4-piperidinyl-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4,4-difluorophenylbutyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and1-[1-(4-phenyl-phenylmethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one.1-[1-(2-napthyl-methyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-benzyloxy-benzyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(decahydronaphyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(2[1,3dihydro-indene])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-isopropylhexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-[1-methyl-ethyl]hexane)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-cyclodecyl-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(3-diphenylpropyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(2-phenylethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(cyclooctylmethyl)-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-[1,2,3,4,hydro-napthyl])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[1-(4-[1-3dimethyl-pentyl])-4-piperidinyl]-3-[1-oxo-ethyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and pharmaceutically acceptable salts thereof.
 13. A pharmaceuticalcomposition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.
 14. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of a compound according to claim
 1. 15. A method of modulating apharmacological response from the ORL1 receptor comprising administeringan effective amount of a compound according to claim
 1. 16. A compoundselected from the group consisting of1-[4-dibenzocycloheptyl-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[4-(4-propylcyclohexane)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[4-(4-propyl-1,2-cyclohexene)-4-piperidinyl-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[4-(4,4-difluorophenylbutyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;1-[4-(4-phenyl-phenyhnethyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzamidazol-2-one;and pharmaceutically acceptable salts thereof.
 16. A pharmaceuticalcomposition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.
 17. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of a compound according to claim
 1. 18. A method of modulating apharmacological response from the ORL1 receptor comprising administeringan effective amount of a compound according to claim
 1. 19. A method ofmodulating a response from opioid receptors comprising administering acompound having a binding affinity for the ORL1 receptor of less than500 K_(i) (nM) and a binding affinity for the mu receptor of less than25 K_(i) (nM).
 20. A method of reducing side effects associated with theadministration of opioid analgesics in a human patient comprisingadministering to said human patient an analgesically effective amount ofa non-opioid compound which exhibits a binding affinity for the ORL1receptor of less than 500 K_(i) (nM).
 21. The method of claim 20 whereinsaid compound has a binding affinity for the mu receptor of less than 25K_(i) (nM).